Hepatic mitochondrial aldehyde dehydrogenase oxidizes acetaldehyde generated in the metabolism of ethanol. One third of Oriental subjects carry an aldehyde dehydrogenase allele that codes for an inactive dehydrogenase. These subjects develop high acetaldehyde levels when consuming ethanol, resulting in a dysphoric state. Homozygotes are virtual abstainers, while heterozygotes for this mainly dominant mutation can consume only limited amounts of alcohol and are largely protected from alcoholism. Disulfiram, a drug which inhibits aldehyde dehydrogenase, is most effective in reducing drinking in alcoholics. However, disulfiram must be taken daily and is metabolized to an active form. Differences in compliance and in metabolism lead to marked inter-individual variation in effects. In addition, disulfiram has a number of side effects, including hypotension and severe neuropathy. Disulfiram administration constitutes the treatment of choice for alcoholism in Scandinavia, but its use has been reduced in the United States. Studies in this application aim at inhibiting hepatocyte mitochondrial acetaldehyde dehydrogenase activity by suppressing aldehyde dehydrogenase gene transcription and translation. Long-lived phosphorothioate oligonucleotides will be tested towards this aim. Studies investigate the effectiveness of (a) triple helix-forming phosphorothioate oligonucleotides which bind to specific DNA regions to inhibit gene transcription (b)antisense phosphorothioate oligonucleotides which bind to mRNA to reduce gene translation. Overall, studies proposed test the general hypotheses that (i) long-lived inhibition of aldehyde dehydrogenase activity can be achieved by inhibition of gene expression, (ii) this inhibition will result in major reductions in voluntary alcohol consumption by animals, compatible with the use of triple helix and antisense phosphorothioate oligonucleotides as anti-alcohol drugs.